The instant invention relates to the use of 4-H-1-benzopyran-4-one derivatives as inhibitors of smooth muscle cell (SMC) proliferation.
The cellular responses to vascular injuryxe2x80x94cellular dysfunction, activation, dedifferentiation, proliferation, and migrationxe2x80x94culminate in clinical events such as restenosis, which occurs following balloon angioplasty and stent placement for the treatment of human atherosclerotic disease1. Smooth muscle cell (SMC) proliferation is a common, and perhaps unifying, feature of vascular injury models, and SMC are the major cellular component of neointimal lesions2,3. Renewed interest in inhibiting SMC proliferation has accompanied the increased use of stents for the treatment of coronary disease, since in-stent restenosis is almost entirely dependent on neointimal formation and SMC hyperplasia4. It is estimated that as many as 100,000 patients with in-stent restenosis required treatment in 1997 alone5; therefore, an easily administered, effective inhibitor of SMC hyperplasia would have profound clinical and economic ramifications6.
Efforts to inhibit SMC proliferation in vascular injury models, either by modulating cellular mediators of the proliferative response or by directly interfering with the cell cycle machinery, have provided important insights into neointimal formation. Cell cycle progression is a tightly controlled event regulated positively by cyclin-dependent kinases (Cdks) and their cyclin regulatory subunits7, and negatively by Cdk inhibitors and tumor suppressor genes such as retinoblastoma protein (Rb) and p538. Adenoviral-mediated overexpression of endogenous Cdk inhibitors p21 and p27kip1 or of a constitutively active form of Rb blocks neointimal formation in the rat carotid injury model9-11; similarly, inhibition of the activity of transcription factor E2F by competitively overexpressing cognate DNA binding sites also inhibits SMC proliferation and neointimal formation12. Such studies support the general hypothesis that cell cycle inhibition is an attractive target for intervention in vascular lesion formation.
Whereas genetic interventions have aided in the dissection of the mechanisms regulating neointimal formation, they suffer from the shortcoming of not being, at present, clinically suitable for the treatment of vascular disease in humans. A water-soluble, low molecular weight compound with specific cell cycle-regulatory effects, particularly one with oral activity, would have broad applicability both experimentally and, potentially, clinically. The recently identified flavone, flavopiridol, is a Cdk inhibitor that potently blocks the activity of Cdk2, Cdc2, and Cdk413-16. In contrast with other pharmacological inhibitors of Cdks, flavopiridol is remarkable for its kinase specificity, its oral availability, and its potency, being effective in nanomolar concentrations16. These unique features result in a favorable side effect profile that has led to the testing of flavopiridol in Phase I clinical trials for the treatment of refractory neoplasms17. Given these properties, we have examined the ability of flavopiridol to inhibit SMC proliferation in vitro and after balloon injury to the rat carotid artery. We demonstrate that flavopiridol is a potent and selective inhibitor of cell cycle progression and that it arrests SMC proliferation both in vivo and in vitro; moreover, neointimal formation is effectively blocked by oral doses of flavopiridol lower than those known to have toxic effects in humans.
It has now suprisingly been found, that 4-H-1-benzopyran4-one derivatives are suitable SMC proliferation inhibitor. It is know that 4-H-1-benzopyran-4-one derivativesare suitable for controlling tumors. However, it is surprising that 4-H-1-benzopyran-4-one derivatives according to the instant invention effectively act as an SMC proliferation inhibitor at dosage level than the dosage levels which have to be used in the control of tumor growth.
Accordingly, a subject of the instant invention is the use of 4-H-1-benzopyran4-one derivatives as inhibitors of smooth muscle proliferation.